A proposed common spatial pharmacophore and the corresponding active conformations of some TxA2 receptor antagonists

Four pharmacophore recognition sites have been proposed for active thromboxane A2 (TxA2) antagonists. We have sought to define the corresponding spatial pharmacophore for these four sites by performing conformational analysis and molecular superposition studies on five known antagonists: SQ 29,548, SQ 28,668, SQ 27,427, BM 13.505, and a Merck Frosst compound. The strategy was to identify a low intramolecular-energy conformer state for each antagonist for which the relative locations and orientations of the corresponding recognition site groups were in common when all five antagonists were superimposed. The conformations used in the successful molecular superpositions were then postulated to be the active conformations of each antagonist. Since SQ 29,548 is the most potent of the five antagonists, it was considered the reference structure in the molecular superposition. A unique spatial pharmacophore was identified and may be a useful template in designing a new TxA2 antagonists.